Context: Pheochromocytomas are catecholamine-producing tumors which are generally benign, but which can also present as or develop into malignancy. Occurrence of malignant pheochromocytomas can only be asserted by imaging of metastatic lesions.

Objectives: We conducted a gene expression profiling of benign and malignant tumors in order to identify a gene signature that would allow to discriminate benign from malignant pheochromocytomas, and to gain a better understanding of tumorigenic pathways associated with malignancy.

Design: 36 patients with pheochromocytoma were studied retrospectively. Eighteen (9 benign and 9 malignant) tumors were used for gene expression profiling on pangenomic oligonucleotide microarrays.

Results: We identified and validated a set of predictor genes that could accurately distinguish the two tumor subtypes through unsupervised clustering. Most of the differentially expressed genes were downregulated in malignant tumors, and several of these genes encoded neuroendocrine factors involved in prominent characteristics of chromaffin cell biology. In particular, the expression of two key processing enzymes of trophic peptides, peptidylglycine alpha-amidating monooxygenase and glutaminyl-peptide cyclotransferase, was reduced in malignant pheochromocytomas.

Conclusions: The gene expression profiling of benign and malignant pheochromocytomas clearly identified a set of genes that could be used as a prognostic multi-marker, and revealed that the expression of several genes encoding neuroendocrine proteins was reduced in malignant compared to benign tumors.